Qingzhi Gao

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Name: 高清志

Organization: Tianjin University , China

Department: School of Pharmaceutical Science and Technology

Title: Professor(PhD)

TOPICS

Organic Chemistry

Ionic Liquid

Chemicals
References

Mechanistic and biological characteristics of different sugar conjugated 2-methyl malonatoplatinum(II) complexes as new tumor targeting agents

Co-reporter:Xiangqian Gao, Shengnan Liu, Yunli Shi, Zhenhua Huang, Yi Mi, Qian Mi, Jinna Yang, Qingzhi Gao

European Journal of Medicinal Chemistry 2017 Volume 125() pp:372-384

Publication Date(Web):5 January 2017

DOI:10.1016/j.ejmech.2016.09.047

•A new series of platinum(II) glycoconjugates derived from different sugar motifs was prepared for tumor targeting.•The conjugates exhibited comparable or better cytotoxicities than oxaliplatin determined in six human cancer cell lines.•The intrinsic DNA reactivity of the conjugates has equal or greater apoptotic potential compared to oxaliplatin.•The cellular uptake the glycoconjugates was regulated by the GLUT mediated transport.•Glu-Me-Pt showed enhanced therapeutic index and antitumor efficacy in vivo compared to cisplatin and oxaliplatin.Novel cis-2-methylmalonato(trans-R,R-cyclohexane-1,2-diamine)platinum(II) glycoconjugates derived from different sugar motifs, namely, glucose (Glu-Me-Pt), mannose (Man-Me-Pt) and galactose (Gal-Me-Pt) were designed and synthesized based on the third generation clinical drug oxaliplatin for potential glucose transporters (GLUTs) mediated tumor targeting. All platinum(II) glycoconjugates were characterized by 1H NMR, 13C NMR, IR, HRMS as well as 195Pt-NMR analysis. Despite their substantial improvement in water solubility, the conjugates exhibited comparable or better in vitro cytotoxicities than oxaliplatin determined in six different human cancer cell lines. Glu-Me-Pt has been shown to be more effective than cisplatin and oxaliplatin with improved therapeutic index in leukemia-bearing DBA/2 mice model. The potential GLUT transportability of the complexes was investigated using cell-based fluorescent competition assay and GLUT inhibitor mediated cell viability analysis in GLUT over-expressing HT29 cell line. Each sugar motif was found to be useful to enable the platinum(II) complexes as substrate for GLUT mediated cell uptake. In vitro DNA adduct formation analysis has been investigated for the first time for this class of compounds to reveal the intrinsic differences in antitumor activity between the malonatoplatinum(II) glycoconjugates and oxaliplatin. The intrinsic DNA reactivity of the platinum(II)-sugar conjugates was found as Gal-Me-Pt > Glu-Me-Pt > Man-Me-Pt ≈ oxaliplatin by kinetic study on the formation of platinum(II) adducts with guanosine-5′-monophosphate (5′-GMP). The results from this study demonstrate the usefulness of glucose, mannose and galactose as alternative sugar motif on glycoconjugation for GLUT mediated drug design and pharmaceutical R&D, and the obtained fundamental results also support the potential of the GLUT targeted platinum(II)-sugar conjugates as lead compounds for further pre-clinical evaluation.

Mannose-conjugated platinum complexes reveals effective tumor targeting mediated by glucose transporter 1

Co-reporter:Ran Liu, Hong Li, Xiangqian Gao, Qian Mi, Hongxia Zhao, Qingzhi Gao

Biochemical and Biophysical Research Communications 2017 Volume 487, Issue 1(Issue 1) pp:

Publication Date(Web):20 May 2017

DOI:10.1016/j.bbrc.2017.04.004

•Mannose-conjugated platinum complexes were designed and synthesized to target glucose transporter 1(GLUT1).•Mannose-conjugated platinum complex 4a transport across cancer cells through GLUT1.•Mannose-conjugated platinum complex 4a induce apoptosis in HT29 cells.•Mannose-conjugated platinum complex 4a antitumor activities were more potent than those of oxaliplatin.Despite numerous studies that report the glucose derived glycoconjugates as antitumor candidates, using mannose as sugar motif for specific tumor targeting remains less studied. In this research, two novel mannose-conjugated platinum complexes 4a and 4b that target the Warburg effect were designed, synthesized and evaluated for their antitumor activities in vitro and in vivo. Compared with oxaliplatin, both complexes exhibited substantial enhancement in water solubility as well as excellent or comparative cytotoxicity in six human cancer cell lines. Cytotoxicity assessments on Glucose transporter 1 (GLUT1) down-regulated or overexpressed cells and platinum accumulation study demonstrated that cellular uptake of compound 4a was regulated by GLUT1. In particular, 4a induced apoptosis in HT29 cells by suppressing expression of Bcl-2 and Bcl-XL, which preliminary explained the mechanism origin of antitumor effect. As indicated by its maximum tolerated dose-finding assay and in vivo anticancer activity, compound 4a exhibits better safety and efficacy profile than oxaliplatin. The findings of this study indicate the possibility of subjecting mannose-conjugated platinum complexes as lead compounds for further preclinical evaluation.Download high-res image (198KB)Download full-size image

Deciphering the origins of molecular toxicity of combretastatin A4 and its glycoconjugates: interactions with major drug transporters and their safety profiles in vitro and in vivo

Co-reporter:Zhenhua Huang;Gentao Li;Xue Wang;Hu Xu;Youcai Zhang

MedChemComm (2010-Present) 2017 vol. 8(Issue 7) pp:1542-1552

Publication Date(Web):2017/07/19

DOI:10.1039/C7MD00246G

Cellular uptake and transport mechanisms directly correlate with the drug-like profiles of lead compounds. To decipher the molecular origin of the toxicity of combretastatin A4 (CA4), an important microtubule targeting agent, we investigated the interactions between CA4 and six key drug transporters, namely hOAT1, hOAT3, hOCT1, hOCT2, hOATP1B3, and hOATP2B1. Three combretastatin-based glycoconjugates, namely Glu-CA4, Man-CA4, and Gal-CA4 with glucose, mannose, and galactose respectively, were synthesized and their in vitro and in vivo biological characteristics were evaluated. CA4 exhibited significant inhibition against hOAT3 and hOATP2B1, moderate inhibition of hOAT1 and hOCT2, and weak inhibitory effects on hOCT1 and hOATP1B3. Compared to CA4, the inhibitory activities of Glu-CA4 on the six transporters were minimal. The glycoconjugates were found to have a superior safety profile with their maximum tolerated dose (MTD) values exhibiting a 16–34-fold increase compared to CA4. Given the drawbacks of CA4, the enhanced solubility and safety profiles of CA4 glycoconjugates augur well for further investigation into these intriguing candidates' in vivo efficacy.

Mechanistic Study of Human Glucose Transport Mediated by GLUT1

Co-reporter:Xuegang Fu; Gang Zhang; Ran Liu; Jing Wei; Daisy Zhang-Negrerie; Xiaodong Jian

Journal of Chemical Information and Modeling 2016 Volume 56(Issue 3) pp:517-526

Publication Date(Web):January 28, 2016

DOI:10.1021/acs.jcim.5b00597

The glucose transporter 1 (GLUT1) belongs to the major facilitator superfamily (MFS) and is responsible for the constant uptake of glucose. However, the molecular mechanism of sugar transport remains obscure. In this study, homology modeling and molecular dynamics (MD) simulations in lipid bilayers were performed to investigate the combination of the alternate and multisite transport mechanism of glucose with GLUT1 in atomic detail. To explore the substrate recognition mechanism, the outward-open state human GLUT1 homology model was generated based on the template of xylose transporter XylE (PDB ID: 4GBZ), which shares up to 29% sequence identity and 49% similarity with GLUT1. Through the MD simulation study of glucose across lipid bilayer with both the outward-open GLUT1 and the GLUT1 inward-open crystal structure, we investigated six different conformational states and identified four key binding sites in both exofacial and endofacial loops that are essential for glucose recognition and transport. The study further revealed that four flexible gates consisting of W65/Y292/Y293-M420/TM10b-W388 might play important roles in the transport cycle. The study showed that some side chains close to the central ligand binding site underwent larger position changes. These conformational interchanges formed gated networks within an S-shaped central channel that permitted staged ligand diffusion across the transporter. This study provides new inroads for the understanding of GLUT1 ligand recognition paradigm and configurational features which are important for molecular, structural, and physiological research of the MFS members, especially for GLUT1-targeted drug design and discovery.

Design, Synthesis of Novel Platinum(II) Glycoconjugates, and Evaluation of Their Antitumor Effects

Co-reporter:Jianbin Han;Xiangqian Gao;Ran Liu;Jinna Yang;Menghua Zhang;Yi Mi;Ying Shi

Chemical Biology & Drug Design 2016 Volume 87( Issue 6) pp:867-877

Publication Date(Web):

DOI:10.1111/cbdd.12718

A new series of sugar-conjugated (trans-R, R-cyclohexane-1, 2-diamine)-2-halo-malonato-platinum(II) complexes were designed and synthesized to target tumor-specific glucose transporters (GLUTs). The water solubility of the sugar-conjugated platinum (II) complexes was greatly improved by average of 570-fold, 33-fold, and 94-fold, respectively, compared to cisplatin (1.0 mg/mL), carboplatin (17.1 mg/mL), and the newest generation of clinical drug oxaliplatin (6.0 mg/mL). Despite the high water solubility, the platinum(II) glycoconjugates exhibited a notable increase in cytotoxicity by a margin of 1.5- to 6.0-fold in six different human cancer cell lines with respect to oxaliplatin. The potential GLUT1 transportability of the complexes was investigated through a molecular docking study and was confirmed with GLUT1 inhibitor-mediated cytotoxicity dependency evaluation. The results showed that the sugar-conjugated platinum(II) complexes can be recognized by the glucose recognition binding site of GLUT1 and their cell killing effect depends highly on the GLUT1 inhibitor, quercetin. The research presenting a prospective concept for targeted therapy anticancer drug design, and with the analysis of the synthesis, water solubility, antitumor activity, and the transportability of the platinum(II) glycoconjugates, this study provides fundamental data supporting the inherent potential of these designed conjugates as lead compounds for GLUT-mediated tumor targeting.

Methyl 6-Amino-6-deoxy-d-pyranoside-Conjugated Platinum(II) Complexes for Glucose Transporter (GLUT)-Mediated Tumor Targeting: Synthesis, Cytotoxicity, and Cellular Uptake Mechanism

Co-reporter:Taoli Li;Xiangqian Gao;Liu Yang;Yunli Shi; Qingzhi Gao

ChemMedChem 2016 Volume 11( Issue 10) pp:

Publication Date(Web):

DOI:10.1002/cmdc.201600079

Abstract

Methyl 6-aminodeoxy-d-pyranoside-derived platinum(II) glycoconjugates were designed and synthesized based on the clinical drug oxaliplatin for glucose transporter (GLUT)-mediated tumor targeting. In addition to a substantial improvement in water solubility, the conjugates exhibited cytotoxicity similar to or higher than that of oxaliplatin in six different human cancer cell lines. GLUT-mediated transport of the complexes was investigated with a cell-based fluorescence competition assay and GLUT-inhibitor-mediated cytotoxicity analysis in a GLUT-overexpressing human colorectal adenocarcinoma (HT29) cell line. The antitumor effect of the aminodeoxypyranoside-conjugated platinum(II) complexes was found to depend significantly on the GLUT inhibitor, and the cellular uptake of the molecules was regulated by GLUT-mediated transport. The results from this study demonstrate the potential advantages of aminodeoxypyranosides as sugar motifs for glycoconjugation for Warburg-effect-targeted drug design. These fundamental results also support the potential of aminodeoxypyranoside-conjugated platinum(II) complexes as lead compounds for further preclinical evaluation.

Glucose conjugated platinum(II) complex: Antitumor superiority to oxaliplatin, combination effect and mechanism of action

Co-reporter:Hong Li, Xiangqian Gao, Ran Liu, Yu Wang, Menghua Zhang, Zheng Fu, Yi Mi, Yiqiang Wang, Zhi Yao, Qingzhi Gao

European Journal of Medicinal Chemistry 2015 Volume 101() pp:400-408

Publication Date(Web):28 August 2015

DOI:10.1016/j.ejmech.2015.07.006

•A highly water soluble glucose conjugated platinum(II) complex was prepared for tumor targeting.•The maximum tolerated dose was 6-fold higher than oxaliplatin.•The in vivo antitumor efficacy in leukemia-bearing DBA/2 mice was greater than oxaliplatin.•The in vitro FOLFOX combination effect against five human cancer cell lines was greater than oxaliplatin.A glucose-conjugate of (trans-R,R-cyclohexane-1,2-diamine)-2-fluoromalonato-platinum(II) complex (Glu-Pt) is designed to target tumor-specific active glucose transporters (GLUTs). Despite of very high water solubility, Glu-Pt exhibits improved cytotoxicity as compared to oxaliplatin. In this study, we investigated the in vivo toxicity profiles with the maximum tolerated dose (MTD) evaluation followed by antitumor efficacy study in leukemia-bearing DBA/2 mice. Glu-Pt showed 6-fold increase in the MTD and was more efficacious against mouse L1210 ascetic leukemia than oxaliplatin at equitoxic doses. To explore the combination effect of Glu-Pt and compare with oxaliplatin-based FOLFOX chemotherapy, we investigated the two-component synergistic antitumor activity of Glu-Pt with folinic acid (FA) and 5-fluorouracil (5-FU) respectively in five human cancer cell lines followed by a comparison study with oxaliplatin in a fixed three-component in vitro FOFLOX combination. As the result, Glu-Pt exhibited superior synergistic cytotoxicity compared to oxaliplatin. Flow cytometry-based cell cycle and apoptosis study demonstrated that Glu-Pt follows the same mechanistic principles as of oxaliplatin. Glu-Pt monotherapy and its combination with FA and 5-FU may result in improved efficacy over oxaliplatin and FOLFOX regimen. The study provides fundamental data supporting the potential of Glu-Pt as a drug candidate for further (pre)clinical development.